Non-specific X-linked semidominant mental retardation by mutations in a Rab GDP-dissociation inhibitor

Thierry Bienvenu, Vincent Des Portes, Anne Saint Martin, Nathalie McDonell, Pierre Billuart, Alain Carrié, Marie Claude Vinet, Philippe Couvert, Daniela Toniolo, Hans Hilger Ropers, Claude Moraine, Hans Van Bokhoven, Jean Pierre Fryns, Axel Kahn, Cherif Beldjord, Jamel Chelly

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Abstract

Non-specific X-linked mental retardation (MRX) is a very common disorder which affects ~1 in 600 males. Despite this high frequency, little is known about the molecular defects underlying this disorder, mainly because of the clinical and genetic heterogeneity which is evident from linkage studies. Recently, a collaborative study using the candidate gene approach demonstrated the presence of mutations in GDIα, a Rab GDP-dissociation inhibitor encoded by a gene localized in Xq28, associated with non-specific mental retardation. GDIα is mainly a brain-specific protein that plays a critical role in the recycling of Rab GTPases involved in membrane vesicular transport. The study presented here was designed to assess the prevalence of mutations in the GDIα in mentally retarded patients and to discuss the clinical phenotypes observed in affected individuals. Mutation screening of the whole coding region of the GDIα gene, using a combination of denaturing gradient gel electrophoresis and direct sequencing, was carried out in 164 patients found negative for expansions across the FRAXA GCC repeat. In addition to the nonsense mutation recently reported in MRX48, we have identified a novel missense mutation in exon 11 of the GDIα gene in one familial form of non-specific mental retardation. In this family (family R), all affected males show moderate to severe mental retardation, and the X-linked semidominant inheritance is strongly suggested by the severe phenotypes in males with respect to mildly affected females or unaffected obligatory carriers. This study showed that the prevalence of GDIα mutations in non-specific mental retardation could be estimated to be 0.5-1%, and molecular diagnosis and genetic counselling in some cases of nonspecific mental handicap can now be provided.

Original languageEnglish
Pages (from-to)1311-1315
Number of pages5
JournalHuman Molecular Genetics
Volume7
Issue number8
Publication statusPublished - Aug 1998

Fingerprint

Guanine Nucleotide Dissociation Inhibitors
X-Linked Mental Retardation
Intellectual Disability
Mutation
Genes
rab GTP-Binding Proteins
Phenotype
X-Linked Genes
Denaturing Gradient Gel Electrophoresis
Genetic Heterogeneity
Nonsense Codon
Mentally Disabled Persons
Genetic Counseling
Recycling
Missense Mutation
Molecular Biology
Exons
Cross-Sectional Studies
Membranes
Brain

ASJC Scopus subject areas

  • Genetics

Cite this

Bienvenu, T., Des Portes, V., Saint Martin, A., McDonell, N., Billuart, P., Carrié, A., ... Chelly, J. (1998). Non-specific X-linked semidominant mental retardation by mutations in a Rab GDP-dissociation inhibitor. Human Molecular Genetics, 7(8), 1311-1315.

Non-specific X-linked semidominant mental retardation by mutations in a Rab GDP-dissociation inhibitor. / Bienvenu, Thierry; Des Portes, Vincent; Saint Martin, Anne; McDonell, Nathalie; Billuart, Pierre; Carrié, Alain; Vinet, Marie Claude; Couvert, Philippe; Toniolo, Daniela; Ropers, Hans Hilger; Moraine, Claude; Van Bokhoven, Hans; Fryns, Jean Pierre; Kahn, Axel; Beldjord, Cherif; Chelly, Jamel.

In: Human Molecular Genetics, Vol. 7, No. 8, 08.1998, p. 1311-1315.

Research output: Contribution to journalArticle

Bienvenu, T, Des Portes, V, Saint Martin, A, McDonell, N, Billuart, P, Carrié, A, Vinet, MC, Couvert, P, Toniolo, D, Ropers, HH, Moraine, C, Van Bokhoven, H, Fryns, JP, Kahn, A, Beldjord, C & Chelly, J 1998, 'Non-specific X-linked semidominant mental retardation by mutations in a Rab GDP-dissociation inhibitor', Human Molecular Genetics, vol. 7, no. 8, pp. 1311-1315.
Bienvenu T, Des Portes V, Saint Martin A, McDonell N, Billuart P, Carrié A et al. Non-specific X-linked semidominant mental retardation by mutations in a Rab GDP-dissociation inhibitor. Human Molecular Genetics. 1998 Aug;7(8):1311-1315.
Bienvenu, Thierry ; Des Portes, Vincent ; Saint Martin, Anne ; McDonell, Nathalie ; Billuart, Pierre ; Carrié, Alain ; Vinet, Marie Claude ; Couvert, Philippe ; Toniolo, Daniela ; Ropers, Hans Hilger ; Moraine, Claude ; Van Bokhoven, Hans ; Fryns, Jean Pierre ; Kahn, Axel ; Beldjord, Cherif ; Chelly, Jamel. / Non-specific X-linked semidominant mental retardation by mutations in a Rab GDP-dissociation inhibitor. In: Human Molecular Genetics. 1998 ; Vol. 7, No. 8. pp. 1311-1315.
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